1. Field of the Invention
The invention relates to the field of pharmaceutical compounds in particular pyrrolidinones and pyrrolidine-thiones and analogs thereof.
The invention further concerns processes for preparing these pharmaceutical compounds, compositions containing them and their use for the treatment and prevention of disease.
2. Summary of the Related Art
Chemokines (chemotactic cytokines) are a large class of proteins that share structural homology and possess chemotactic activity for a variety of cell types (Luster, A. (1998), N. Eng. J. Med. 338:436; Kim, C. and Broxmeyer, H. (1999), J. Leuk. Biol. 65: 6.). They are divided into four groups based on the number and positioning of the first two cysteines of their sequence. The two major groups are the CC or beta chemokines (having two adjacent cysteines) and the CXC or alpha chemokines (X representing a single amino acid in between the cysteines). Examples of the former group include MIP-1α, MIP-1β, RANTES, MCP-1, (Kim, ibid; Strader, C. et al (1995), FASEB J. 9: 745; Salcedo, R. et al (2000), Blood 96: 34), Eotaxin, TARC, MDC, MIP-3α, MIP-3β and I-309. Examples of the latter group include IL-8, NAP-1, MGSA-α, β, and γ, ENA-78, IP-10, Mig, I-TAC, SDF-1 and BLC. In addition to the CC and CXC chemokines, two other types of chemokine are known, each consisting of a single known chemokine. Fractalkine is a CX3C type, having three amino acids between its first two cysteines, and lymphotactin is a C type chemokine having only one cysteine in the N-terminal domain.
Numerous chemokine receptors have been identified and extensively characterized with respect to the chemokines they bind and the cells on which they are expressed. These receptors (CCRs, CXCRs, CX3CRs and CRs, depending on which type of chemokine they bind) exhibit a significant degree of sequence homology. Chemokine receptors are members of the large receptor family known as G-protein coupled receptors (GPCRs)( Strader, C. et al (1995), FASEB J. 9: 745), which are characterized by having seven-transmembrane helical domains and being functionally associated with heterotrimeric GTP-binding proteins (G-proteins). The existence of such a variety of chemokines (over 40) and chemokine receptors (at least 19 have been identified), in addition to their differential expression on specific cell types, provides for enormous diversity and specificity of ligand-receptor interactions. Consequently, the biological functions mediated by these proteins are diverse and complex.
MCP-1 is a chemokine produced by a number of cell types, including macrophages, mast cells, epithelial cells, endothelial cells, and fibroblasts and astrocytes. It is a potent chemoattractant for a number of different types of immune cells, such as monocytes, macrophages, activated T cells, basophils, and immature dendritic cells. MCP-1 has also been shown to induce biological responses in endothelial cells and astrocytes (Salcedo, R. et al (2000), Blood 96: 34; Dorf, M. et al (2000), J. Neuroimmunol. 111: 109). MCP-1 binds to CCR2 and, to date, no other high affinity receptor specific for MCP-1 has been confirmed. CCR2 is constitutively expressed in many immune cells and is also up-regulated under inflammatory conditions. CCR2 is also expressed in the human monocytic cell line THP-1 (Van Riper, G. et al (1993), J. Exp. Med. 177: 851).
It is well established that MCP-1 is a central factor in the immunoregulation of inflammatory responses. Numerous studies in animals have demonstrated the direct effect of MCP-1 on the infiltration of immune effector cells in vivo. For example, transgenic mice expressing MCP-1 in specific tissues exhibit an enhanced localized infiltration of monocytes in those tissues (Gu, L. et al (1997), J. Leuk. Biol. 62: 577; Gunn, M. et al (1997), J. Immunol. 158: 376). Injection of MCP-1 protein into animals has also been shown to induce the infiltration of basophils and T cells (Taub, D. et al (1995), J. Clin. Invest. 95: 1370; Conti, P. et al (1997), Int. Immunol. 9: 1563; Kuntsfeld, R. et al (1998), J. Invest. Dermatol. 111: 1040). Knockout mice lacking either MCP-1 (Lu, B. et al (1998), J. Exp. Med. 187: 601) or CCR2 (Kurihara, T. et al (1997), J. Exp. Med. 186: 1757; Kuziel, W. et al (1997), Proc. Nat. Acad. Sci. USA 94: 12053) exhibit a reduction in the extravasation and tissue infiltration of monocytes and macrophages in response to inflammatory stimuli. Neutralization of MCP-1 with monoclonal antibodies has been shown to inhibit the infiltration of monocytes (Ajuebor, M. et al (1998), J. Leuk. Biol. 63: 108) and T cells (Rand, M. et al (1996), Am. J. Pathol. 148: 855) in experimentally-induced models of inflammation in animals.
The immune response to pathogens initially involves presentation of antigen to CD4+ T cells followed by clonal expansion and differentiation of the T cells into Th1 and Th2 subpopulations (Paul, W. (1992), in Inflammation, J. Gallin, I. Goldstein, and R. Snyderman (eds), pp 775-790. Raven Press; Abbas, A. et al (1996), Nature 383: 787). The two T cell subsets produce different types of cytokines that mediate the induction of different types of immune responses. Th1 cells produce IFNα, IL-2, IL-12, and TNFβ which function to generate antiviral immunity in the form of cytotoxic T cells, natural killer cells, and antibody subclasses that mediate antibody dependent cellular cytotoxicity (ADCC). Th2 cells produce IL-4, IL-5, IL-10, and IL-13, which generate allergic and anti-parasitic immune responses by inducing the proliferation and activation of eosinophils and mast cells and the synthesis of IgE antibodies. MCP-1, in addition to its direct effect on the migration of monocytes and T cells, has been shown to play a part in the regulation of T cell responses. MCP-1 has been shown to bias differentiation of activated T cells towards the Th2 phenotype, both in vitro and in vivo (Karpus, W. et al (1997), J. Immunol. 158; 4129; Gu, L. et al (2000), Nature 404: 407).
The production and biological activity of MCP-1 makes it a central player in the pathogenesis of inflammatory diseases by acting at many levels. For example, in atopic asthma, exposure to allergen induces immediate release of MCP-1 by activated mast cells and MCP-1 production at later times by epithelium and endogenous macrophages. MCP-1 subsequently induces the chemotaxis of T lymphocytes, macrophages and basophils into the challenged tissues and induces T cells to differentiate to the Th2 subtype. This results in the generation of IL-4 and IL-5 and, subsequently, the production of IgE and the proliferation and migration of eosinophils. These coordinated biological responses, centrally mediated by MCP-1, lead to the infiltration and activation of immune effector cells, increased sensitization of mast cells in the lung, and maintenance of the asthmatic condition.
It is evident that CCR2 is an appropriate target for inhibiting the excessive inflammatory responses that contribute to disease. The present invention is based on the discovery of compounds that antagonize CCR2. By antagonizing this receptor, the compounds block the biological effects of MCP-1 and thus inhibit the inflammatory processes mediated by the chemokine.
Published International Patent Application No. WO 95/19362 describes generically certain dihydropyrrole derivatives as intermediates. Said compounds are disclosed solely as racemates and no reference is made to isomers or isomerism. Furthermore, the only compounds of this type specifically disclosed in WO 95/19362 are unsubstituted in the 5-position of the dihydropyrrole ring.
The synthesis of certain 1,5-dihydro-2H-pyrrol-2-ones is known from: Zh. Org. Khim. (1986) 22: 1749-1756; Zh. Org. Khim (1986) 22: 1790-1791; Khim. Geterotsikl. Soedin. (1987) 5: 625-628; Zh. Org. Khim. (1988) 24: 875-881; Khim.-Farm. Zh. (1991) 25: 37-40; Zh. Org. Khim. (1992) 28: 779-785; Khim.Geterotsikl. Soedin. (1992) 1: 32-36: Zh. Obshch. Khim. (1992) 62: 2633-2634; Heterocycles (1993) 36: 2541-2547; Russian J. Gen Chem. (1994) 64: 1084-1086: Chem. Heterocycl. Compd. (1998) 34: 739; Russian J. Gen. Chem. (1999) 69: 668-669. The synthesis of certain 3-amino-2-mercaptopyrroles is known from Phos. Sulf. Silic. Relat. Elem. (1999) 148: 117-130.
Compound 1 in the table disclosed hereinafter was purchased from Biospecs in Rijswijk, The Netherlands and compounds 2, 3, 4 and 122 in the table disclosed hereinafter were purchased from Ambinter in Paris, France.
In none of these instances is reference made to pharmaceutical compositions comprising the compounds or to their use as pharmaceuticals.